The goal of this application is to answer clinically and scientifically important questions about the role of calcium-phosphorus homeostasis in the development of cardiovascular disease. First, we will determine the associations between parathyroid hormone (PTH) and the development of coronary heart disease (CHD) and hypertension. By direct or indirect actions on bone, kidney, and intestine, PTH plays a central role in calcium and phosphorus balance. However, the PTH receptor also is expressed in vascular smooth muscle and the endothelium, and PTH increases the endothelial expression of factors implicated in endothelial dysfunction and atherosclerosis, such as endothelin-1, the receptor of advanced glycation end products, and IL-6. Second, we will clarify the independent associations between plasma levels of 25-hydroxyvitamin D (25[OH]D), calcium, phosphorus, PTH, creatinine and incident CHD. Previous prospective studies of calcium-phosphorus metabolism and CHD risk did not simultaneously measure these interrelated factors. Finally, we aim to resolve existing controversies about supplemental calcium use, phosphorus intake and the risk of incident CHD. We plan to conduct prospective nested case-control studies of the independent associations between plasma levels of intact PTH, 25(OH)D, calcium, and phosphorus and the risk of CHD and hypertension in the Health Professionals Follow-up Study (HPFS;N=51,529 men) and the Nurses'Health Study (NHS;N=121,700 women). We also plan to conduct prospective cohort studies examining the relations between supplemental calcium use, phosphorus intake, and incident CHD. Because previous data suggest an association between PTH and hypertension in men but not pre-menopausal women, we will determine whether the impact of PTH on the risk of hypertension in post-menopausal women varies by use of post-menopausal hormones. This application represents the first large-scale prospective effort to examine the impact of PTH on CHD risk in individuals without primary hyperparathyroidism or chronic kidney disease. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. PUBLIC HEALTH RELEVANCE: We expect our studies of calcium and phosphorus metabolism to provide new insights into the development of cardiovascular disease and to identify several novel and modifiable coronary heart disease risk factors. Our findings may stimulate future research that eventually allows factors regulating calcium- phosphorus balance to serve as targets for the prevention of coronary heart disease and hypertension.